Insulin binding Autophosphorylation of insulin receptor PathwayStep5111 PathwayStep5110 PathwayStep5117 PathwayStep5050 PathwayStep5049 Internalisation of the insulin receptor Insulin receptor recycling Signaling by Insulin receptor Authored: Bevan, AP, 2003-07-31 08:01:55 Edited: Schmidt, EE, 0000-00-00 00:00:00 GENE ONTOLOGYGO:0008286 Insulin binding to its receptor results in receptor autophosphorylation on tyrosine residues and the tyrosine phosphorylation of insulin receptor substrates (e.g. IRS and Shc) by the insulin receptor tyrosine kinase. This allows association of IRSs with downstream effectors such as PI-3K via its Src homology 2 (SH2) domains leading to end point events such as Glut4 translocation. Shc when tyrosine phosphorylated associates with Grb2 and can thus activate the Ras/MAPK pathway independent of the IRSs.<p>Signal transduction by the insulin receptor is not limited to its activation at the cell surface. The activated ligand-receptor complex initially at the cell surface, is internalised into endosomes itself a process which is dependent on tyrosine autophosphorylation. Endocytosis of activated receptors has the dual effect of concentrating receptors within endosomes and allows the insulin receptor tyrosine kinase to phosphorylate substrates that are spatially distinct from those accessible at the plasma membrane. Acidification of the endosomal lumen, due to the presence of proton pumps, results in dissociation of insulin from its receptor. (The endosome constitutes the major site of insulin degradation). This loss of the ligand-receptor complex attenuates any further insulin-driven receptor re-phosphorylation events and leads to receptor dephosphorylation by extra-lumenal endosomally-associated protein tyrosine phosphatases (PTPs). The identity of these PTPs is not clearly established yet. A discussion of candidates will be added in the near future. Insulin receptor mediated signaling Reactome Database ID Release 4374752 Reactome, http://www.reactome.org ReactomeREACT_498 Reviewed: Barroso, I, Stanley, FM, 0000-00-00 00:00:00 Insulin receptor signalling cascade